A Quick Reminder in Seconds:
In Part One of this three-part series, we encountered the story of a remarkable toad photographed by Canadian photojournalist Scott Gardner in 1992. It appeared so unusual that many people assumed it was a hoax or a practical joke. The toad in the photograph had no visible eye sockets; instead, both of its eyes appeared to be embedded in the roof of its mouth. The image quickly spread across Canada and the United States and later appeared in scientific publications and popular science books. Initially baffled by the toad’s unusual features, scientists considered the possibility that this rare condition resulted from a major developmental abnormality—sometimes described in terms of “macromutations.” In this article, we will take a closer look at developmental biology, explain what macromutations are, and explore their possible causes and consequences.
Solving the Mystery
The answer to the mystery of the Canadian toad lies in one of the most fascinating fields of biology: embryonic development [1].
From the moment a fertilized egg begins dividing, an extraordinary process unfolds. A complete animal does not emerge simply because every organ is pre-programmed to appear in a fixed location according to a genetic blueprint. Instead, the embryo develops through an intricate conversation among its cells. As they divide, migrate, and specialize, neighboring cells continuously exchange molecular signals that tell one another what they should become, when they should develop, and precisely where they should form. This remarkable process, known as embryonic induction [2], allows billions of cells to work together to construct a complex living organism.
Equally important are the embryo’s developmental control genes [3], sometimes called master regulatory genes [4]. Rather than building organs directly, these genes coordinate the countless genetic instructions that guide the body’s overall plan. They regulate when cells divide, where they migrate, and how tissues and organs are organized. If one of these regulatory genes—or the signaling pathways it controls—is disrupted early in development, the effects can spread throughout the embryo, producing dramatic structural abnormalities rather than the small genetic variations that commonly occur within populations.
The development of the eye provides one of the classic demonstrations of this process.
Early in embryonic development, a small outgrowth from the developing brain forms a structure called the optic vesicle [5]. The optic vesicle later develops into the retina and associated structures of the eye. During this process, the developing eye tissues send molecular signals that influence the overlying surface tissue, the ectoderm [6], directing it to develop into the lens. Without these signals, the lens does not form normally.
In other words, developing eye tissues communicate with neighboring tissues and help direct them to construct the rest of the eye.
Developmental biologists demonstrated this principle through a series of elegant experiments. When developing eye tissue was transplanted to an unusual location in a frog embryo—for example, near the future mouth—it could continue sending developmental signals. Nearby cells could respond to those signals by producing a lens and other eye structures in an abnormal location.
These experiments revealed an important truth: genes alone do not determine where organs develop. Continuous communication between neighboring tissues is also essential.
The remarkable toad photographed by Scott Gardner appears to illustrate, in an extraordinarily dramatic way, what can happen when normal developmental processes go awry. Instead of developing in their normal position on the sides of the head, the eyes apparently formed within the roof of the mouth. This suggests that the developmental signals and tissue interactions that normally guide eye formation may have been disrupted or redirected during early embryonic development.
What Is a Macromutation?
Researchers have suggested that such a rare condition could be associated with a macromutation [7]—a term historically used to describe a relatively large genetic change capable of producing a substantial effect on an organism’s body structure. Unlike the much smaller genetic changes often referred to as micromutations [8], which can contribute to subtle variations among individuals, a macromutation can produce a striking change in anatomy or development.
The term macromutation has an interesting scientific history. Some early evolutionary biologists proposed that entirely new species might arise through single, dramatic mutations. Modern evolutionary and developmental biology does not generally support that view as a general explanation for the origin of complex new body plans. Today, the term is used more cautiously, particularly when discussing unusually large phenotypic changes associated with genetic or developmental alterations.
What Causes Macromutations?
Exactly what triggers severe developmental abnormalities remains uncertain, and in many cases, no single cause can be identified. Scientists recognize that genetic and environmental factors can interact during the earliest stages of embryonic development.
One possibility is a mutation affecting a developmental regulatory gene, such as one of the HOX genes [9], or another regulatory gene involved in organizing the body’s overall structure. Because developmental regulatory genes can influence the activity of many other genes, alterations in these systems can sometimes produce widespread anatomical changes.
Developmental abnormalities may also arise without an inherited mutation. Errors in cell migration, tissue folding, signaling, or organ formation during embryonic development can sometimes redirect normal growth into unexpected patterns.
Environmental factors may further increase the risk of developmental abnormalities. One well-known example involves parasitic flatworms called trematodes [10]. Their microscopic larvae can infect developing tadpoles and have been associated with severe limb deformities, including extra legs, missing or shortened limbs, and other skeletal abnormalities.
Pollution may make matters even worse. Agricultural pesticides, industrial chemicals, and fertilizer runoff can affect amphibian health and aquatic ecosystems while potentially altering the abundance or distribution of aquatic snails that serve as intermediate hosts for some trematode species. Greater exposure to parasites, combined with chemical stress, may therefore contribute to developmental abnormalities.
Other possible contributors include increased ultraviolet (UV-B) radiation, toxic contaminants, viral infections, and physical injury to embryos during the earliest stages of development. Because these influences can occur together, scientists can rarely identify a single cause responsible for an individual developmental abnormality.
But can a frog with two eyes inside its mouth lead a normal life? And why are scientists interested in studying such rare cases? That’s what we’ll find out in Part Three.
Notes
1. Embryonic Development
Embryonic development is the process by which a fertilized egg develops into an embryo through cell division, differentiation, and the formation of tissues and organs. It involves precisely coordinated genetic and molecular signals that guide cells toward their specific structures and functions.
2. Embryonic Induction
Embryonic induction is a process in which one group of embryonic cells influences the development and specialization of another group of cells. These interactions help determine what tissues and organs will form in particular locations during embryonic development.
3. Developmental Control Genes
Developmental control genes are genes that regulate the timing, location, and pattern of cellular development in an embryo. By controlling other genes and cellular processes, they help determine how tissues and organs form and develop.
4. Master Regulatory Genes
Master regulatory genes are genes that act high in the hierarchy of developmental control, activating or regulating networks of other genes involved in forming particular structures or tissues. A single master regulatory gene can therefore have a major influence on the developmental fate of a group of cells.
5. Optic Vesicle
The optic vesicle is an early embryonic structure that develops as an outgrowth from the forebrain. It later gives rise to major parts of the eye, including the retina and the retinal pigment epithelium.
6. Ectoderm
Ectoderm is the outermost of the three primary germ layers formed during early embryonic development. It gives rise to structures such as the epidermis of the skin, the nervous system, and parts of the eyes and other sensory organs.
7. Macromutation
A macromutation is a relatively large genetic change that can produce a substantial alteration in an organism’s developmental pattern or physical characteristics. Such changes can result from major alterations in genes, chromosomes, or regulatory regions and are generally much less common than small genetic changes.
8. Micromutations
Micromutations are small genetic changes that usually produce relatively minor alterations in an organism’s characteristics. They may involve changes in individual DNA bases or small DNA sequences and can contribute to gradual variation within populations.
9. HOX Genes
HOX genes are a group of developmental control genes that help determine the identity and organization of body regions along the head-to-tail axis of an embryo. They act by regulating other genes and are highly conserved across many animal species, reflecting their fundamental role in body-plan development.
10. Trematodes
Trematodes, commonly known as flukes, are parasitic flatworms belonging to the class Trematoda. Many species live inside the tissues or body fluids of vertebrate hosts and have complex life cycles that often involve one or more intermediate hosts, such as snails.
References
1. The Travel Staff. “A photographer in Canada found a toad with eyes in its mouth, and scientists were baffled.” The Travel, June, 24, 2026.
https://www.thetravel.com/photo-of-toad-with-eyes-in-mouth-found-in-canada
2. Developmental Biology. (2020). Developmental Biology (12th ed.). Sinauer Associates / Oxford University Press.
3. Principles of Development. (2019). Principles of Development (6th ed.). Oxford University Press.
4. John Gerhart, J., & Marc Kirschner, M. (1997). Cells, Embryos, and Evolution. Blackwell Science.
5.. Langman’s Medical Embryology. (2024). Langman’s Medical Embryology (15th ed.). Wolters Kluwer.